Vindesine (4-desacetyl VLB C-3 carboxamide) has the following structure ##STR1##
Vindesine was first described by Cullinan and Gerzon, Belgian Pat. No. 813,168, as one member of a new group of vinca alkaloid derivatives, the C-3 carboxamides. Methods heretofore utilized for the preparation of vindesine have included: reaction of VLB and ammonia in a sealed tube (partial hydrolysis of the C-4 acetyl group takes place during the reaction and/or work-up); reaction of VLB with hydrazine hydrate to yield 4-desacetyl VLB C-3 carboxhydrazide (with hydrazine, hydrolysis of the C-4 acetyl is virtually complete) followed by reaction with nitrous acid to give the C-3 carboxazide which is in turn reacted with ammonia to yield the C-3 carboxamide; and hydrogenolysis of 4-desacetyl VLB C-3 carboxhydrazide prepared as above with Raney nickel by the procedure of Ainsworth, U.S. Pat. No. 2,756,235, to yield vindesine directly. Each of these procedures suffers from one or more disadvantages. For example, it is very difficult to scale-up a Raney nickel production process and yeilds of desired products differ from batch to batch of Raney nickel. A reliable process suitable for manufacturing vindesine on a commercial scale is clearly needed. Direct reaction of VLB with ammonia yields a mixture of products, etc.
Vindesine is now undergoing extensive clinical trial as an oncolytic agent, particularly for the treatment of leukemia, in the United States and abroad. The compound approachs the activity of vincristine in the treatment of leukemia but with a somewhat different spectrum of side-effects. In addition, certain vincristine-resistant leukemias have been found to be susceptible to vindesine treatment. Finally there is an indication of vindesine activity against both oat-cell and non-oat cell carcinomas of the lung.
It is an object of this invention to provide a commercially feasible synthesis of vindesine which gives highly reproducible yields of the desired product and is accompanied by a minimum number of those by-products which are difficult to remove from vindesine by chromatography.